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Diagnostic Value of Strand-Specific Mirna-101-3P and Mirna-101-5P

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Diagnostic Value of Strand-Specific Mirna-101-3P and Mirna-101-5P Diagnostic value of strand-specific miRNA-101-3p and miRNA-101-5p for hepatocellular carcinoma and a bioinformatic analysis of their possible mechanism of action Xia Yang1,†, Yu-Yan Pang1,†, Rong-Quan He2, Peng Lin3, Jie-Mei Cen2, Hong Yang3, Jie Ma2,# and Gang Chen1,# 1 Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, China 2 Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, China 3 Department of Ultrasonography, First Affiliated Hospital of Guangxi Medical University, Nanning, China Keywords There is accumulating evidence that miRNA might serve as potential diag- bioinformatics; Gene Expression Omnibus; nostic and prognostic markers for various types of cancer. Hepatocellular hepatocellular carcinoma; microRNA-101-3p; carcinoma (HCC) is the most common type of malignant lesion but the sig- microRNA-101-5p; The Cancer Genome nificance of miRNAs in HCC remains largely unknown. The present study Atlas aimed to establish the diagnostic value of miR-101-3p/5p in HCC and then Correspondence further investigate the prospective molecular mechanism via a bioinformatic J. Ma, Department of Medical Oncology, analysis. First, the miR-101 expression profiles and parallel clinical parame- First Affiliated Hospital of Guangxi Medical ters from 362 HCC patients and 50 adjacent non-HCC tissue samples were University, Shuangyong Road 6, Nanning, downloaded from The Cancer Genome Atlas (TCGA). Second, we aggre- Guangxi, China gated all miR-101-3p/5p expression profiles collected from published litera- Tel: +86 771 5312980 ture and the Gene Expression Omnibus and TCGA databases. Subsequently, E-mail: [email protected] G. Chen, Department of Pathology, First target genes of miR-101-3p and miR-101-5p were predicted by using the Affiliated Hospital of Guangxi Medical miRWalk database and then overlapped with the differentially expressed University, Shuangyong Road 6, Nanning, genes of HCC identified by natural language processing. Finally, bioinfor- Guangxi, China matic analyses were conducted with the overlapping genes. The level of miR- Tel: +86 771 5356534 101 was significantly lower in HCC tissues compared with adjacent non- E-mail: [email protected] HCC tissues (P < 0.001), and the area under the curve of the low miR-101 † level for HCC diagnosis was 0.925 (P < 0.001). The pooled summary receiver These authors contributed equally to this work. #These authors contributed equally to this work. operator characteristic (SROC) of miR-101-3p was 0.86, and the combined SROC curve of miR-101-5p was 0.80. Bioinformatic analysis showed that the (Received 19 March 2017, revised 8 May target genes of both miR-101-3p and miR-101-5p are involved in several 2017, accepted 8 November 2017) pathways that are associated with HCC. The hub genes for miR-101-3p and miR-101-5p were also found. Our results suggested that both miR-101-3p doi:10.1002/2211-5463.12349 and miR-101-5p might be potential diagnostic markers in HCC, and that they exert their functions via targeting various prospective genes in the same pathways. Abbreviations AFP, alpha-fetoprotein; AUC, area under the curve; BP, biological process; CC, cellular component; CI, confidence interval; CNKI, Chinese National Knowledge Infrastructure; DAVID, Database for Annotation, Visualization and Integrated Discovery; FN, false negative; FoxO, forkhead box O; FP, false positive; GEO, Gene Expression Omnibus; GO, Gene Ontology; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; KEGG, Kyoto Encyclopedia of Genes and Genomes; MAPK, mitogen-activated protein kinase; MF, molecular function; NLP, natural language processing; NLR, negative likelihood ratio; PI3K, phosphoinositide-3-kinase; PLR, positive likelihood ratio; PPI, protein– protein interaction; pre-miRNA, precursor miRNA; ROC, receiver operating characteristic; SROC, summary receiver operator characteristic; TCGA, The Cancer Genome Atlas; TN, true negative; TP, true positive. 64 FEBS Open Bio 8 (2018) 64–84 ª 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. X. Yang et al. Diagnostic value and bioinformatics analysis of miR-101 in HCC According to Cancer Statistics, 2017 [1], the incidence miRNA, they may have different target genes and bio- rates of liver cancer in the USA continue to increase logical functions. A previous study [20] reported that rapidly (~ 3% per year in women and 4% per year in the expression levels of the miR-5p and miR-3p men), and the death rate rose by almost 3% per year mature sequences can be altered in different tissues. from 2010 to 2014. In addition, the mortality rate is Accumulating evidence [19,21–25] has shown that three times higher in men than in women. Since Asia is miR-101-3p/-5p is down-regulated in multiple malig- the area with the highest incidence rate of liver cancer, nances, including HCC. For example, Hou et al. [26] especially China, annual incidence and mortality are explored miRNA expression profiling and revealed more than half of the global totals [2]. Among the three that miR-101 (3p and 5p were not distinguished) histological types of liver malignancy, hepatocellular expression in HCC tissues was lower than in healthy carcinoma (HCC) has become the leading cause of controls. Wei et al. [27] also showed that miR-101 (3p death from cancer. Since there have been no biomarkers and 5p were not distinguished) was down-regulated in or common surgical techniques for the early stage of HBV-associated HCC tissues and may have therapeu- HCC, the majority of patients with HCC are diagnosed tic potential in HCC. Additionally, the function of late, which directly correlates with a poor outcome and these miRNAs has also been investigated. Zhang et al. low survival rate. As with other cancers, HCC develop- [28] revealed that enforced expression of miR-101 (3p ment is a multistep process with abundant genetic and and 5p were not distinguished) by siRNA inhibited the epigenetic mutations. A recent study confirmed that cell proliferation and tumorigenicity of an HCC cell hepatocarcinogenesis can be caused by chronic hepatitis line in vitro. Sheng et al. [29] investigated how miR- B virus (HBV) infection [3]. Much effort towards the 101-3p regulated cell proliferation, cell cycle and apop- treatment of HBV-infected HCC has been made in the tosis in HCC and found that overexpression of miR- past, but with only limited success. Thus, identifying 101-3p caused an enhanced rate of apoptosis but no novel biochemical markers for early HCC diagnosis is a obvious change in the cell cycle. Besides, several onco- matter of the utmost urgency. genes, such as EZH2, FOS, COX-2 and SOX9, have miRNAs, ~ 20–22 nucleotides in length, are a class been found to be directly regulated by miR-101-3p/5p of small endogenous non-coding RNA molecules. [30–32]. Recently the potential of the miR-101 family They post-transcriptionally regulate mRNA expression as diagnostic indicators has also caught the eye of through imperfect base paring with the 30-untranslated researchers. He et al. [33] conducted a meta-analysis region of target genes. With comprehensive study, that summarized miRNAs’ diagnostic value in HCC miRNAs have become known as the star molecules of and found that miR-101-5p had great diagnostic value, cancer research. miRNAs in human cancers are though only three data sets were included and the involved in several pivotal biological processes (BP), results need to be further validated. Furthermore, in including cancer proliferation, differentiation, progres- human, miR-101 precursor transcripts are encoded sion and cell apoptosis [4–6]. Although their functions with two genomic loci (miR-101-1 and miR-101-2). remain elusive, up- and down-regulation of miRNAs For two mature miRNAs, miR-101-3p is generated have been widely reported in all kinds of cancer tissues from the 30 ends of the precursors, and miR-101-5p in comparison with expression in the corresponding from the 50 end of pre-miR-101-1 (http://www.mirbase. normal tissues [7,8]. In particular, miRNAs have been org/). We speculated that miR-101-3p may also serve found to be biomarkers for cancer clinical diagnosis, as a diagnostic marker for HCC. Since the seed region histological classification and prognosis [9–13]. of miR-101-3p and miR-101-5p is unique, they are pre- Accumulating evidence has clearly demonstrated dicted to regulate unique targets. However, to the best that the aberrant expression of miRNAs may further of our knowledge, the comparative roles of miR-101- influence the expression of tumor oncogenes and sup- 3p and miR-101-5p in HCC have not yet been fully pressor genes, thereby leading to the occurrence of a studied. tumor [14–17]. Theoretically, mature miRNA genera- The present study investigated miR-101-3p and tion requires a series of enzyme reactions. First, pri- miR-101-5p expression in HCC tissues compared with mary miRNA transcripts are cleaved in the nucleus by that in healthy controls. Published studies, Gene the Drosha enzyme to liberate the precursor miRNA Expression Omnibus (GEO) microarray chips and The (pre-miRNA) hairpin. Subsequently, the pre-miRNA Cancer Genome Atlas (TCGA) data that included is exported to the cytoplasm and further processed by miR-101-3p or miR-101-5p expression information the enzyme Dicer to produce two mature miRNAs were collected together. Additionally, previous studies (miR-5p and miR-3p) [18,19]. Even though the two have mainly focused on a single gene [34–36], and mature miRNAs are transcribed from the same pre- studies have rarely focused on the function of FEBS Open Bio 8 (2018) 64–84 ª 2017 The Authors.
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